Serotonergic modulation of the BNST-CeA pathway reveals sex differences in fear learning

Post-traumatic stress disorder (PTSD) is characterized by intense fear memory formation and is diagnosed more often in women than men. Here we show that increasing serotonin pharmacologically before auditory fear conditioning promoted memory recall in female and male mice, and that females were more sensitive to this effect. Optogenetic stimulation of raphe terminals in the anterior dorsal bed nucleus of the stria terminalis (adBNST) during fear conditioning increased c-Fos expression in the BNST and central nucleus of the amygdala (CeA) and enhanced fear memory recall through activation of 5-HT_2C receptors in the adBNST in females only. Likewise, serotonin stimulation during fear learning enhanced adBNST-CeA high gamma (90-140 Hz) synchrony and adBNST-to-CeA communication in high gamma during fear memory recall in females only. These findings suggest that sex differences in the raphe-BNST-CeA pathway may contribute to the higher risk of PTSD in women.